Engineered nanomaterials, including carbon nanotubes (CNT), have unique physicochemical properties with potential to impact diverse aspects of society. While there are currently over 800 products on the market that contain nanomaterials, there is a significant lack of toxicity testing associated with these products despite emerging observations of adverse respiratory and cardiovascular effects associated with nanomaterials. In addition, due to their unique properties, nanomaterials have the potential to interact with biological systems in a distinctive manner. However, to date there is only a limited understanding of how nanomaterials interact with biological systems; and therefore we lack the ability to predict which nanomaterials are safe and which are toxic; and how nanomaterials might be engineered to avoid toxic side effects. Inhalation of single-walled CNT (SWCNT) or multi-walled CNT (MWCNT) has been reported to cause lung inflammation and fibrosis. In addition, recent work in our laboratory suggests that exposure to MWCNT impacts the cardiovascular system. Mast cells may well be critical effector cells in inducing these toxic effects. We have preliminary, but convincing evidence that CNT pulmonary exposure activates resident mast cells, either directly or indirectly, thereby contributing to both pulmonary and cardiovascular pathology. Our preliminary findings support the hypothesis that CNT exposure activates mast cells through an IL-33 dependent mechanism which results in pulmonary inflammation and adverse cardiovascular events due to the resultant release of inflammatory mediators, including osteopontin (OPN). We will test this hypothesis by: 1) examining mast cell activation in lungs of mice exposed to MWCNTs; 2) examining the role of IL-33 in mediating mast cell activation; 3) elucidating the role of mast cells in contributing to altered vascular reactivity within the cardiovascular system; 4) using cell based models to establish the mechanisms by which MWCNTs lead to mast cell activation. This proposal is novel in that it identifies an unrecognized, yet significant mechanism by which CNTs lead to toxicity. Understanding this mechanism will allow us to design better models and in vitro screening tools to predict nanomaterial toxicity. Lastly, this proposal provides an important translational application in that by elucidating the proposed mechanism, we will provide support for the use of mast cell directed strategies, such as cromolyn sodium, to intervene early after exposure to prevent subsequent inflammation and fibrosis. PUBLIC HEALTH RELEVANCE: The use of engineered nanomaterials in the biotechnology industry and manufacturing setting has increased dramatically in recent years. Yet, the properties that make nanoparticles useful in science and medicine also present potential safety concerns. This proposal will elucidate a mechanism, involving mast cell activation, by which multi-walled carbon nanotubes elicit pulmonary and cardiovascular toxicities. Completion of this proposal will provide the data needed to assess the toxicity associated with additional nanomaterials and will provide important translational implications as the data will begin to support the notion that early intervention with mast cell directed medicines following nanotube exposure may provide beneficial therapy.